Fibroblast growth factor (FGF) pathways in general are implicated in many physiological processes, such as morphogenesis during development and angiogenesis which is the process of developing new blood vessels that involves the proliferation, migration, and tissue infiltration of capillary endothelial cells from pre-existing blood vessels. FGFs are some of the factors that have been implicated as possible regulators of angiogenesis along with transforming growth factor (TGF), vascular endothelial growth factor (VEGF), and platelet derived growth factor (PDGF). FGF pathways are also implicated in neuronal survival and wound healing. They are also thought to be important in a number of pathological processes.
In particular, FGFR-1 has been implied to be involved in diseases such as cancers and arthritis. Although the involvement of FGF pathways in metabolism, such as feeding behavior and adipose tissue development has been suggested, it is not clear whether these findings entail fundamental mechanisms through which metabolism is regulated. For example, a recent study performed in mice has shown that injections of FGF-2, in combination with basement membrane proteins, can induce development of new adipose tissue at the site of the injection. This suggests that locally produced FGFs may act in a paracrine manner to affect adipogenesis and thereby influence the regional distribution of adipose tissue in the body and the relationship between adipose tissue and insulin resistance is well-established, both of which are strongly implicated in type 2 diabetes and cardiovascular disease.
Fibroblast growth factor receptors (FGFRs) have common structural features and consist of an extracellular ligand-binding domain containing 2 or 3 Ig-like loops and a unique acid region, a trans-membrane domain, and the cytoplasmic region, which contains the tyrosine kinase catalytic domain and kinase insert. The FGFRs belong to Subclass IV of the receptor tyrosine kinase family of proteins. These receptors bind in an overlapping pattern to FGFs. It has been established that 22 FGFs act on 5 FGFRs in FGF ligand paracrine interaction.
FGFR-1 has two alternative splicing forms that differ from each other by the amino acid substitutions in the third IgG-like domain of the extracellular structure of the receptor designated IIIb and IIIc, FGFR-4 has only one. These substitutions constitute what is believed to be part of the binding domain of the receptor, and therefore are most likely to cause the two splicing forms to have distinct ligand specificities. The two forms have also been shown to be differentially expressed, which may be part of an exquisite control mechanism of complex functions mediated by FGFR-1.
Ligand binding, which is strengthened by the presence of heparin sulfate, causes the FGFRs to dimerize and activate specific intracellular signaling pathways (Bellot et al. 1991). The receptor becomes auto-phosphorylated and thus capable of activating downstream cellular pathways. Among different cellular responses, stimulation of proliferation or induction of differentiation is most commonly observed for FGFR-1 mediated signaling.